Project description:The aim of our study was to investigate whether miRNAs could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with KRAS wild-type (wt-KRAS) metastatic colorectal cancer (mCRC). In our study, historical cohort of 96 patiens with wt-KRAS mCRC (2006-2009) was included and further divided into exploratory and validation cohorts. Large-scale miRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 30 patients of wt-KRAS mCRC treated with cetuximab and 25 patients of wt-KRAS mCRC treated with panitumumab.
Project description:MicroRNA microarray profilling analysis was performed on exosomes derived from serum in patients with myeloma in two conditions of therapeutic efficacy, Bortezomib resistance and Bortezomib response. Bortezomib is approved and widely used treating myeloma.
Project description:MicroRNA microarray profilling analysis was performed on exosomes derived from serum in patients with myeloma in two conditions of therapeutic efficacy, Bortezomib resistance and Bortezomib response. Bortezomib is approved and widely used treating myeloma. Two kinds of sample were analyzed. MicroRNA microarray profilling analysis (using miRCURY LNA microRNA Array, 7th generation REV - hsa, mmu & rno, mirBase release 18, ProductNumber=208520,208521,208522) was performed on exosomes derived from serum in patients with myeloma in two conditions of therapeutic efficacy, Bortezomib resistance and Bortezomib response.
Project description:Here, we report the genomic-scale characterization of locally advanced colon cancer transcriptome. Paraffin embedded samples was used to asses differences between normal colon, primary colon tumor an lymph node metastasis.
Project description:Gene expression profile (GEP) was analyzed from cultured bone marrow (BM) samples from patients with bortezomib responsive versus bortezomib resistant myeloma after 6-8 hours incubation in vitro with bortezomib 2 µg/ml or with PBS. Case D also had a fresh BM sample taken 75 minutes after IV injection of bortezomib.
Project description:In managing patients with rat sarcoma virus (RAS) wild-type (WT) metastatic colorectal cancer (mCRC), monoclonal antibodies against the epidermal growth factor receptor (EGFR) represent a key therapeutic strategy. However, their limited ongoing effectiveness in this setting underscores the importance of elucidating other factors that affect response, including underlying immunological and metabolic repertoires. An emerging therapeutic target, glutamine metabolism is crucial for cancer cell growth; symbiotically, tumor glutamine demand relative to the microenvironment disadvantages potential anti-tumor immunity. We conducted a phase I/II clinical trial in patients with RAS WT mCRC combining panitumumab, an EGFR inhibitor, and CB-839, a glutaminase inhibitor, hypothesizing that antagonizing glutamine-centric tri-carboxylic acid (TCA) cycle metabolism and mitogen-activated pathway kinase (MAPK)-mediated growth would favor response in well-selected patients. Here, we demonstrate that a novel B cell activation signature, ‘Bscore’ was associated with clinical benefit from combined therapy in patients who previously progressed on anti-EGFR therapy. Patient ‘Bscore’ was positively associated with treatment-induced change in lesion size. Furthermore, patients with lower ‘Bscore’ tended to exhibit greater tumor avidity of glutamine by non-invasive positron emission tomography (PET), suggesting the sensitivity of B cell activation to a glutamine-depleted microenvironment and highlighting future opportunities to enhance immune response in the treatment of mCRC and potentially other glutaminolysis-dependent solid tumors.
Project description:Platinum-based chemotherapy plus cetuximab, an anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody (Mab), is usually offered to recurrent/metastatic (R/M) head-neck squamous cell carcinoma (HNSCC) patients, with only a small portion experiencing durable responses. The anti-EGFR-Mab panitumumab, was used as single agent in platinum pre-treated R/M-HNSCC patients in a phase II trial (PANI01). By analyzing gene expression profiles of a selected retrospective series of HNSCC patients treated with cetuximab, an anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody (MAb), associated to chemotherapy, we were able to propose that long progression-free survival (PFS) cases consistently belong to defined molecular subtypes, such as Cluster3-hypoxia and Basal subtypes, respectively defined by De Cecco et al [DeCecco; Oncotarget, 2015] and Keck et al [Keck; CCR,2015], while short-PFS cases are characterized by an over-activation of RAS signaling
Project description:The proteasome is an appealing anti-cancer drug target and the proteasome inhibitor bortezomib has been approved for the treatment of certain types of malignancies. However, the molecular mechanisms underlying cancer cell resistance to bortezomib remain poorly understood. The pseudokinase TRIB3, an inhibitor of ATF4, is expressed at a high basal level in hepatoma cells and is strongly upregulated in response to bortezomib. To map genome-wide chromatin binding loci of TRIB3 protein, we fused a Flag tag to endogenous TRIB3 in HepG2 cells and performed ChIP-Seq. The results demonstrate that TRIB3 predominantly colocalizes with ATF4 on chromatin and the proteins reside in genomic regions containing the C/EBP-ATF motif. Bortezomib treatment leads to a robust enrichment of TRIB3 binding near genes induced by bortezomib and involved in the ER stress response and cell death. Disruption of TRIB3 increases C/EBP-ATF-driven transcription, augments ER stress and cell death in cells exposed to bortezomib, while TRIB3 overexpression enhances the cell survival. Thus, TRIB3, colocalizing with ATF4 and limiting its transcriptional activity, functions as a factor increasing resistance to bortezomib, while pharmacological over-activation of eIF2alpha-ATF4 can overcome the endogenous restraint mechanisms and sensitize cells to bortezomib.
Project description:BACKGROUND: The molecular mechanism of proteasome inhibitor-mediated anti-cancer activity has been logically hypothesized that the major pathway is inhibition of nuclear factor kappa-B (NF-kB) cascades, however, the precise mechanism is still unclear. Adult T-cell leukemia (ATL) is a fatal neoplasia derived from HTLV-1 infected T lymphocytes exhibiting constitutive activation of NF-kB. AIM: To elucidate the complex molecular mechanism of anti-tumor effect of the proteasome inhibitor, bortezomib in ATL cells, we attempted to perform network-based gene expression profiling. METHODS and RESULTS: Assessment of gene regulation by microarray analysis revealed that down-regulation of genes involved in anti-apoptosis (i.e., BCL2, and IAP5), up-regulation of genes related with apoptosis (i.e., FAF1), heat shock proteins (i.e., HSPA, HSPCA), and oxygen stress (i.e., heme oxygenase-1: HMOX-1). Gene network analysis employing the Bayesian statistical framework also suggests that HMOX-1 which is known as an inducer of reactive oxygen species (ROS), as well as SPARC play an important role in bortezomib-treated ATL cells. The HMOX-1 inhibitor, ZnPP, in addition to bortezomib partially inhibited the apoptotic effect of bortezomib on TaY cells. CONCLUSION: Our results suggest that in addition to the inhibition of NF-kB, bortezomib activated ROS pathway through HMOX-1, and SPARC may participate bortezomib-induced apoptosis, providing novel insight into the bortezomib mediated anti-tumor activity in ATL cells. Keywords: dose response and time course
Project description:This experiment is designed to evaluate gene expression alterations following treatment with gambogic acid and bortezomib in human HepG2 cells. We find gambogic acid yielded a similar gene expression profile as did bortezomib. Total RNA were extracted from human HepG2 cancer cells treated with gambogic acid (0.25μM, 0.5μM, 0.75μM) or bortezomib (50nM) for 9hr. HepG2 cells treated with vehicle alone was used as a control.